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Sorting soluble tumor necrosis factor (TNF) receptor for storage and regulated secretion in hematopoietic cells.

Gao, Ying LU ; Hansson, Markus LU ; Calafat, Jero; Tapper, Hans LU and Olsson, Inge LU (2004) In Journal of Leukocyte Biology 76(4). p.876-885
Abstract
Hematopoietic cells contain secretory lysosomes that degranulate at sites of inflammation. We envisage that secretory granules can act as vehicles for targeting inflammatory sites, including malignancies, and thereafter, locally release therapeutically active agents to these sites. Exogenous proteins, such as the soluble tumor necrosis factor receptor 1 (sTNFR1), have been shown previously to be targeted to secretory lysosomes [1]. In this work, we asked whether exogenons, secretory lysosome-targeted proteins were subject to regulated secretion. sTNFR1-transmembrane (tm)cytosol-sorting signal (Y) and sTNFR1-tm-Y-enhanced green fluorescent protein (egfp) were expressed in rat basophilic leukemia cell clones having different secretory... (More)
Hematopoietic cells contain secretory lysosomes that degranulate at sites of inflammation. We envisage that secretory granules can act as vehicles for targeting inflammatory sites, including malignancies, and thereafter, locally release therapeutically active agents to these sites. Exogenous proteins, such as the soluble tumor necrosis factor receptor 1 (sTNFR1), have been shown previously to be targeted to secretory lysosomes [1]. In this work, we asked whether exogenons, secretory lysosome-targeted proteins were subject to regulated secretion. sTNFR1-transmembrane (tm)cytosol-sorting signal (Y) and sTNFR1-tm-Y-enhanced green fluorescent protein (egfp) were expressed in rat basophilic leukemia cell clones having different secretory capacities. sTNFR1-tm-Y was targeted directly from the Golgi to secretory lysosomes, followed by generation of membrane-free sTNFR1, whose secretion could be triggered by a Ca2+ ionophore or inummoglobulin E receptor activation. In contrast, sTNFRI-tm-Y-egfp was targeted to the plasma membrane and then subjected to endocytosis and presumably, secretory lysosome targeting, as judged by results from antibody ligation and cell-surface biotinylation. Activation of protein kinase C with phorbol ester promoted ectodomain shedding at the cell surface, resulting in sTNFR1 release from sTNFR1-tm-Y-egfp. These results support a concept for using the storage organelles of hematopoietic cells as vehicles for targeting sites of inflammation with therapeutically active agents. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
secretary lysosome, endosome pathway, inflammation
in
Journal of Leukocyte Biology
volume
76
issue
4
pages
876 - 885
publisher
Society for Leukocyte Biology
external identifiers
  • wos:000224183100015
  • scopus:4744359700
ISSN
1938-3673
DOI
10.1189/jlb.1103593
language
English
LU publication?
yes
id
7286ab52-b431-4ffd-8907-c648f5cea6b1 (old id 125929)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15240756&dopt=Abstract
date added to LUP
2007-07-04 16:05:47
date last changed
2017-01-01 04:28:03
@article{7286ab52-b431-4ffd-8907-c648f5cea6b1,
  abstract     = {Hematopoietic cells contain secretory lysosomes that degranulate at sites of inflammation. We envisage that secretory granules can act as vehicles for targeting inflammatory sites, including malignancies, and thereafter, locally release therapeutically active agents to these sites. Exogenous proteins, such as the soluble tumor necrosis factor receptor 1 (sTNFR1), have been shown previously to be targeted to secretory lysosomes [1]. In this work, we asked whether exogenons, secretory lysosome-targeted proteins were subject to regulated secretion. sTNFR1-transmembrane (tm)cytosol-sorting signal (Y) and sTNFR1-tm-Y-enhanced green fluorescent protein (egfp) were expressed in rat basophilic leukemia cell clones having different secretory capacities. sTNFR1-tm-Y was targeted directly from the Golgi to secretory lysosomes, followed by generation of membrane-free sTNFR1, whose secretion could be triggered by a Ca2+ ionophore or inummoglobulin E receptor activation. In contrast, sTNFRI-tm-Y-egfp was targeted to the plasma membrane and then subjected to endocytosis and presumably, secretory lysosome targeting, as judged by results from antibody ligation and cell-surface biotinylation. Activation of protein kinase C with phorbol ester promoted ectodomain shedding at the cell surface, resulting in sTNFR1 release from sTNFR1-tm-Y-egfp. These results support a concept for using the storage organelles of hematopoietic cells as vehicles for targeting sites of inflammation with therapeutically active agents.},
  author       = {Gao, Ying and Hansson, Markus and Calafat, Jero and Tapper, Hans and Olsson, Inge},
  issn         = {1938-3673},
  keyword      = {secretary lysosome,endosome pathway,inflammation},
  language     = {eng},
  number       = {4},
  pages        = {876--885},
  publisher    = {Society for Leukocyte Biology},
  series       = {Journal of Leukocyte Biology},
  title        = {Sorting soluble tumor necrosis factor (TNF) receptor for storage and regulated secretion in hematopoietic cells.},
  url          = {http://dx.doi.org/10.1189/jlb.1103593},
  volume       = {76},
  year         = {2004},
}